Role of the Pou4 (Brn3) and Islet transcription factors in the development of the brainstem, spinal cord and sensory systems
In a seminal series of studies between 1995 and 2011, we defined the essential role of the transcription factors Brn3a and Islet1 in the differentiation of peripheral sensory neurons and brainstem. These studies included innovative use of microarrays and chromatin immunoprecipitation to define gene regulatory programs in transgenic mice. Our interest in the habenula began with a project in which identified Brn3a as a key regulator of habenula development (medial plus lateral), required for the distinctive pattern of gene expression in this region. This study, and the resulting collaboration with the Allen Institute for Brain Science, provided the basis for the experimental models we use to study habenula function. A few examples of the resulting publications follow:
- Eng SR, Lanier J, Fedtsova N, Turner EE. Coordinated regulation of gene expression by Brn3a in developing sensory ganglia. Development 2004;131:3859-70.
- Sun Y, Dykes IM, Liang X, Eng SR, Evans S, and Turner EE. A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs. Nature Neuroscience 2008;11: 1283-1293. PMCID: PMC2605652.
- Quina LA, Wang S, Ng L and Turner EE. Brn3a and Nurr1 mediate a gene regulatory pathway for habenula development. J. Neuroscience 2009; 29, 14309-14322. PMCID: PMC2802832.
- Dykes IM, Tempest L, Lee S-I, and Turner EE. Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation. J. Neuroscience 2011; 31:9789-99. PMCID: PMC3143040.
Mechanisms of birth defects affecting craniofacial structures and cranial nerves
Hmx1 is a transcription factor gene known to regulate external ear development in mice, rats and cattle, and is responsible for oculoauricular syndrome (OAS) in humans. We first identified Hmx1 as a downstream target of Brn3a in the developing trigeminal ganglion. In Quina, et al., 2012a, we defined the role of this factor in cranial ganglion development. In collaborative work with the Cox laboratory here at CDBRM we identified a mutation in an ultraconserved enhancer in rats that phenocopies Hmx1 loss of function, one of only a few known examples of enhancer mutations that have clear Mendelian inheritance.
- Quina LA, Tempest L, Hsu Y-W, Cox TC, Turner EE. Hmx1 is required for the normal development of somatosensory neurons in the geniculate ganglion. Developmental Biology 2012; 365:152-163. PMCID: PMC3710741.
- Quina LA, Kuramoto T, Luquetti DV, Cox TC, Serikawa T, and Turner EE. Deletion of a conserved regulatory element required for Hmx1 expression in craniofacial mesenchyme in the dumbo rat: a novel cause of congenital ear malformation. Disease Models and Mechanisms 2012; 6:812-22. PMCID: 3484864.
- Cox TC, Camci ED, Vora S, Luquetti DV, Turner EE. The genetics of auricular development and malformation: New findings in model systems driving future directions for microtia research. European Journal of Medical Genetics 2014; 57:394-401. PMCID: PMC4143470.
- Rosin JM, Li W, Cox L, Rolfe SM, Latorre V, Akiyama JA, Visel A, Kuramoto T, Bobola N, Turner EE, and Cox TC. A distal 594 bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by the Hox-Pbx-Meis complex. Development 2016; 143:2582-2592. PMCID: PMC4958336